The invention generally relates to the filtration of liquids, more particularly to high precision separation suitable for use in the pharmaceutical and biotechnology industries. The invention is especially applicable to filtration through a porous membrane sheet or a porous hollow fiber column. With the invention, a variety of separation techniques are handled in a quantitative manner and can be automated, including having the separation proceed until a desired level of purity or other characteristic or parameter is attained. The invention automates separation processes such as microfiltration, microparticle coating and washing, ultrafiltration, diafiltration and certain preparative chromatography applications. It also automates and optimizes viral infection of mammalian cells such as in gene therapy research and development, as well as rapid cell separation, protein clarification and protein concentration.
In the pharmaceutical and biotechnology industries, the use of micro-filtration, ultrafiltration, tangential or cross-flow filtration, as well as constant volume diafiltration are well-established methods for the separation of dissolved molecules and/or suspended particulates. Typically, the liquid to be filtered is forced through a porous membrane sheet or a porous hollow fiber column. Such sheets or membranes are commercially available in different pore sizes. Depending upon the selected pore size, molecules or particulates smaller than the average membrane or column pore size will pass, together with solvent for example, through the membrane or hollow fiber walls. These molecules or particulates are collected as filtrate, while the retentate is left behind. Many filtration approaches, such as those incorporating ultrafiltration or tangential-flow filtration devices, the retentate is repeatedly re-circulated with the objective of improving filtration efficiency and enhancing the yield of the filtrate or permeate.
However, filtration devices tend to clog when used over an extended period of time and must be timely replaced. Clogging of a filtration device occurs when the membrane pores become obstructed, typically with trapped cells, particulate matter, cell debris or the like. This clogging of the pores results in a decreased liquid flow across the porous membrane sheet or hollow fiber column wall. The result is the development of a back pressure increase which, if not properly addressed, runs the risk of serious detriment to the operation which incorporates the filtration procedure.
Attempts to address these concerns and difficulties have included the development and use of semi-automated filtration systems. These types of systems utilized either manually controlled recirculation pumps or pumps which are controlled by a timing device which will stop pump action after a preset filtration time has elapsed. It is also typical to monitor back pressure through the use of an analog or a digital pressure gauge, usually located between the pump and the filter device. When the gauge reads a certain back pressure level, typically one specified by the manufacture of the filter device, the filtration must be stopped and the old filter must be replaced with a new one. At times, it is not possible to accurately predict the time at which the pumping action must be stopped in order to avoid overtaxing the filter device. Accordingly, prior art systems which rely solely on timing are not entirely satisfactory.
Prior art filtration technology such as that referred to above also is disadvantageous because it is typically very labor intensive. This prior technology also has additional, serious shortcomings for safe and efficient operation. One shortcoming is that the filtrate yield is frequently not quantitative because of unpredictable solution particulate loads. Thus, for a given re-circulation volume and pump rate, the filtrate yield may differ from case to case, depending upon the amount of pore-sized particulate suspended in the recirculation solution. Another shortcoming is a direct result of back pressure build up due to clogging. Rapid back pressure build up at times causes bursting of the filter membrane and/or the filter housing, resulting in costly spillage and/or filtrate contamination. Excessive filter back pressure also frequently leads to blow-off of tube connections such as at the filter inlet, resulting in costly spillage of retentate, for example. Because of these types of shortcomings, manual and semi-automated filtration systems need to be constantly monitored, which greatly contributes to the high labor intensity of such approaches.
Accordingly, there is a need for filtration arrangements which provide for quantitative capability with back pressure monitoring. Desirably, such a filtration approach allows for rapid and safe filtration without concern of losing product, particularly pharmaceutical products or biotechnology products which can be extremely expensive, difficult to replace, and can represent the investment of many hours of prior processing. It would be advantageous to provide systems or procedures which are useful in preventing costly spills. It would also be desirable to provide a filtration approach which can coax the maximum life out of a filtration device without running the risk of generating operational conditions which can lead to excessive back pressure build up near the end of the life of the filtration device.
It has been found that, by proceeding in accordance with the present invention, it is possible to achieve quantitative filtration of liquids in an automated, labor unintensive manner, all while enhancing the safety of the operation while virtually eliminating spillage risks due to overextending the capabilities of the filtration device for handling the particular liquid being filtered and the particular parameters of the filtration system.